Pimecrolimus is an anti-inflammatory compound derived from the macrolactam natural product ascomycin, produced by certain strains of Streptomyces. Pimecrolimus is sold in the United States under the brand name ELIDEL®, and is approved for the treatment of atopic dermatitis. The systematic name of pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl ]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone. Pimecrolimus is the 32-epichloro derivative of ascomycin. Its empirical formula is C43H68ClNO11 and its molecular weight is 810.47.
European Patent EP 427 680 B1 discloses a method of synthesizing pimecrolimus in the form of a colorless foamy resin. The disclosed method comprises the following four reaction steps:    (a) protection of the two hydroxyl groups at C-24 and C-32 with t-butyldimethylsilyl ethers;    (b) deprotection of the silyl-protected hydroxyl group at C-32, while the hydroxyl group at C-24 remains protected;    (c) substitution of chlorine for the free hydroxyl group at C-32 with an inversion of configuration; and    (d) deprotection of the silyl-protected hydroxyl group at C-24.
EP 427 680 does not disclose the yield of each step in the synthesis, but does disclose that each step is followed by the chromatographic purification of the product of that step. Accordingly, it would be expected that the overall yield of the process disclosed in EP 427 680 is low, given the number of reaction steps and chromatographic purifications required.
Therefore, a process for the preparation of pimecrolimus having a reduced number of steps, particularly chromatographic steps, would be advantageous. The present invention provides such processes.